Resistance to VEGF-targeted therapy is a major challenge in the contemporary treatment of mRCC, and endoglin activation may be an important mechanism leading to resistance. Endoglin is an essential angiogenic receptor expressed on proliferating tumor vessels and RCC stem cells, and is upregulated following VEGF inhibition. TRC105 is an endoglin monoclonal antibody that potentiates the anti-tumor activity of bevacizumab and VEGF receptor tyrosine kinase inhibitors in preclinical models. 18 patients were enrolled in phase 1b trial and, TRC105 dose escalation proceeded from 8 mg/kg (n = 3) to 10 mg/kg (n = 15) without dose limiting toxicity. TRC105 at its RP2D of 10 mg/kg was well tolerated with axitinib (A) 5 mg BID in RCC patients. Dose escalation of A to 10 mg BID was possible with the RP2D of TRC105. In phase 1b, the combination of TRC105 and A demonstrated preliminary evidence of activity, including partial responses in 29% of patients by RECIST 1.1, and longer PFS than expected with A as a single agent. The overall disease control rate (CR/PR/SD > 2 months) was 88% (15 of 17). Median PFS overall was 8.4 months, and was 9.6 months among patients with clear cell RCC. Adverse events characteristic of each drug were not increased in frequency or severity when the two drugs were administered concurrently, and most commonly included epistaxis, diarrhea, fatigue, headache, and gingival bleeding.
Phase 2 is a multicenter study that is actively enrolling at this time across approximately 30 sites in the US. In phase 2, 150 patients are randomized 1:1 to A +/- TRC105. Key inclusion criteria: 1 prior VEGF inhibitor, clear cell RCC, ECOG ≤ 1; one prior mTOR and one prior immune therapy are allowed. Primary endpoint is PFS and secondary endpoints are ORR, disease control rate, and to characterize the pharmacokinetic profile of TRC105 and A. (NCT01806064).
Clinical trial identification
Protocol # 105RC101 (NCT01806064)
Legal entity responsible for the study
TRACON Pharmacuticals, Inc. Lead PI: Toni Choueiri
TRACON Pharmacuticals, Inc.
T. Choueiri: Consulting or Advisory Role: Pfizer, Novartis, GSK, Merck, BMS, Roche, Eisai, Prometheus Labs, Inc., Foundation Medicine Inc. Cerulean Research Funding (Institution): Pfizer, Novartis, Merck, Exelixis, TRACON, GSK, BMS, AstraZeneca, Peloton, Roche. N. Agarwal: Consultancy to Pfizer, Exelixis, Argos, Cerulean, and Medivation. S.K. Pal: consulting for Pfizer. B. Seon: patents - roswell park cancer institute. M. Jivani, B. Adams, C. Theuer: Employee of TRACON Pharmaceuticals, Inc. Stock ownership in TRACON Pharmaceuticals, Inc. R. Shazer: Employee of TRACON Pharmaceuticals, Inc. Stock ownership in BMS All other authors have declared no conflicts of interest.